tbuckley/cabot-search huggingface dataset:
PATH-20. CILIA-ASSOCIATED GENE EXPRESSION PREDICTS SURVIVAL IN LOW-GRADE GLIOMAS
Authors: Christian Kaculini, Komudi Singh, Megan Springer, Mi-Yeon Jung, Kory Johnson, Desmond Brown
Journal: Neuro-Oncology (2022)

Abstract Low-grade gliomas (WHO II and III) encompass a histopathologically and clinically heterogeneous constellation of neoplasms. Molecular biomarkers play an increasingly important role in glioma classification, therapy, and prognostication. Primary cilia are microtubule-based organelles that regulate several canonical signal transduction cascades and they have been implicated in the pathogenesis of many malignancies. We hypothesized that LGGs differentially express ciliary genes resulting in unique molecular and prognostic clusters. Four-hundred-sixty-seven LGG patients within The Cancer Genome Atlas (TCGA) were stratified based on differential expression of cilia-associated genes. Four statistically distinct clusters (P &amp;lt; 0.0001) were identified including a high- (median overall survival [OS] 95.5 months; CI [52.1-NA]), mid- (median OS 63.5 months; CI [43.9-NA]) and a low-surviving (median OS 23.7 months; CI [19-134]) cluster. OS was independent of IDH status, 1p/19q codeletion or MGMT promoter methylation status on multivariate analysis. Orthogonal validation was performed using 442 LGGs from the Chinese Glioma Genome Atlas (CGGA). Again, four discrete clusters were found including a high- (median OS 78.4 months, CI [45.8-NA]) and a low-surviving (median OS 16.5 months, CI [12.2-25.5]) cluster. While LGGs with 1p/19q codeletions were present in all clusters, they were overrepresented in the high-surviving groups. The most robustly differentially expressed genes were compared across clusters to find cluster-defining genes most associated with OS. LGGs in the high-surviving group are defined by the expression profiles of 13 genes while low-surviving LGGs are identified by the differential expression of 15 non-overlapping genes. LGGs can be classified into four distinct clusters that are independently associated with OS based on cilia-associated gene expression alone. Within these clusters, there is a high- and a low-surviving group, each with their own unique genetic profiles. These new molecular markers may inform novel therapeutic targets and predictors of clinical outcomes.
QOL-02. FACTORS INFLUENCING COMPLIANCE IN TTF TREATMENT – THE COMPTUNE STUDY
Authors: Martin Proescholdt, Melissa Schmidmeier, Christian Doenitz, Nils-Ole Schmidt, Andreas Mühlberger
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Recently, tumor treating fields (TTFields) were established for the treatment of newly diagnosed glioblastoma (nGBM). A crucial parameter for TTFields efficacy is compliance to treatment. In this prospective study, we assessed 5 psychological domains known to influence treatment compliance using a standardized interview in nGBM patients. The results of this psychological assessment were correlated to TTF compliance. METHODS A cohort of 49 nGBM patients (female 22; male 27, median age 62 years) were recruited. Most patients received a gross total resection (51%), the postsurgical treatment consisted of concomitant radiochemotherapy plus TTF in most cases (81%), only 2 patients received chemotherapy only, and 7 patients were additionally enrolled in clinical drug trials. The psychological assessment system consisted of 5 domains: Social support, confidence in treatment efficacy, communication status about treatment, anxiety, and depression. The interview was repeated every 8 weeks over a period of 8 months or if patients stopped treatment or developed second tumor progression. Additional phone interviews were conducted every 4 weeks. RESULTS Median and mean compliance was 98% and 81.6%, respectively (range 5%-100%), drops of compliance below 75%, which were classified as a threshold value, occurred 2259 times. Over-dispersed Poisson and multivariate negative binomial regression analysis revealed depression to be significantly correlated with the number of drops below 75% and with the mean compliance in the first 4 months of treatment. In addition, at later time points, confidence in treatment efficacy significantly correlated with the number of drops below 75%. All other domains did not appear to be associated with TTF treatment compliance. CONCLUSION Overall, compliance to TTF was high, however, drops below 75% of compliance occurred frequently during the measurement periods. In the initial treatment phase, depression was associated with these events, whereas confidence in treatment efficacy was correlated at later time points.
NCOG-35. A SINGLE INSTITUTION SERIES ON PINEAL PARENCHYMAL TUMORS OF INTERMEDIATE DIFFERENTIATION (PPTID)
Authors: Mason Webb, Jian Campian, Ugur Sener
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION First classified in 2000, pineal parenchymal tumor of intermediate differentiation (PPTID) is an uncommon intracranial malignancy. Given recent codification and rarity, there is no consensus on management and treatment is often provider dependent. METHODS Within an institutional database, we identified 10 patients with PPTID diagnosed between 2009 and 2022. Medical records were reviewed for demographic data, presenting symptoms, extent of disease, surgical interventions, radiation therapy, and chemotherapy. Progression free survival, overall survival, and neurocognitive outcomes were reviewed. RESULTS Median age at diagnosis was 36 (range 13-73), 40% women, 60% Caucasian. Nine patients had tumor involvement limited to the pineal region and one patient had multifocal intracranial tumor involvement with leptomeningeal disease. Two patients had gross total resection (GTR) alone, three had GTR followed by adjuvant radiation therapy (RT), two had subtotal resection (STR) followed by craniospinal irradiation (CSI), two had biopsy followed by adjuvant RT, and one had biopsy with CSI and chemotherapy. At median follow up of 31 months (range 3-88 months), only one patient, who had received biopsy, CSI, and chemotherapy, had progression of disease and no patients are deceased. Two patients treated with CSI had adverse neurocognitive outcomes, which was not observed with focal RT. CONCLUSIONS Our limited case series suggests GTR followed by surveillance, GTR followed by focal RT, and any extent resection followed by CSI may all achieve durable disease control in patients with PPTID. Treatment selection should be individualized and potential neurocognitive toxicities should be considered.
NIMG-40. RAPID EARLY PROGRESSION (REP) OF GLIOBLASTOMA IS AN INDEPENDENT NEGATIVE PROGNOSTIC FACTOR: RESULTS FROM A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Mueez Waqar, Federico Roncaroli, Eric Lehrer, Joshua Palmer, Javier Villanueva-Meyer, Steve Braunstein, Emma Hall, Marianne Aznar, Philip Witt De Hamer, Pietro D'Urso, Daniel Trifiletti, Alfredo Quiñones-Hinojosa, Pieter Wesseling, Gerben Borst
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION In patients with newly-diagnosed glioblastoma, rapid early progression (REP) refers to tumour regrowth between surgery and postoperative chemoradiotherapy. This systematic review and meta-analysis appraised published data on REP to better characterise and understand it. METHODS Systematic searches of MEDLINE, EMBASE and the Cochrane database from inception to 21/10/21. Studies describing the incidence of REP – tumour growth between the postoperative MRI scan and pre-radiotherapy MRI scan in newly-diagnosed glioblastoma, were included. The primary outcome was REP incidence. RESULTS From 1590 search results, 9 studies were included with 716 patients. The median age was 56.9 years (IQR 54.0-58.8 years). There was a male predominance with a median male-to-female ratio of 1.4 (IQR 1.1-1.5). The median number of days between MRI scans was 34 days (IQR 18-45 days). The mean incidence rate of REP was 45.9% (range 19.3%-72.0%) and significantly lower in studies employing functional imaging to define REP (p&amp;lt; 0.001). REP/non-REP groups were comparable with respect to age (p=0.99), gender (p=0.33) and time between scans (p=0.81). REP was associated with shortened overall survival (HR 1.78, 95% CI 1.30-2.43, p&amp;lt; 0.001), shortened progression-free survival (HR 1.78, 95% CI 1.30-2.43, p&amp;lt; 0.001), subtotal resection (OR 6.96, 95% CI 4-51-10.73, p&amp;lt; 0.001) and IDH wildtype versus mutant tumours (OR 0.20, 95% CI 0.02-0.38, p=0.03). MGMT promoter methylation was not associated with REP (OR 1.29, 95% CI 0.72-2.28, p=0.39). CONCLUSIONS REP occurs in almost half of patients with newly-diagnosed glioblastoma and has a strongly negative prognostic effect. Future studies should investigate its biology and effective treatment strategies.
NIMG-93. CORRELATING RELATIVE LEVEL OF IMMUNOCOMPETENCE FOR CNS LYMPHOMA BY RADIOLOGIC CHARACTERISTICS: A CASE SERIES
Authors: Laila Koduri, Kanika Gupta, Makenna Katz, Christopher Trevino
Journal: Neuro-Oncology (2022)

Abstract Radiologically, central nervous system lymphoma (CNSL) presents differently in immunocompetent versus immunosuppressed states. Most patients with immunocompetent CNS lymphoma present with a solitary, deep, homogeneously enhancing lesion while patients with immunocompromised CNS lymphoma frequently have multifocal, centrally necrotic enhancing brain lesions. To date, there have been no radiologic features described along a spectrum of relative levels of immunocompetence. A single institution review on twelve patients with primary and secondary CNSL included clinical factors at diagnosis that are associated with varying levels of relative immunocompromised state. We collected qualitative data on age, prior cancer, radiation, chemotherapy, HIV, diabetes mellitus, steroid/immunosuppressant use, and quantifiable data including white blood cell, neutrophil, and lymphocyte counts. These factors were stratified for severity and correlated with findings on imaging. Our study identified patients with a minor level of immunocompromised state were more likely to develop multifocal disease, while patients with more severe immunocompromised states were likely to develop necrosis. Although our study is limited as a retrospective analysis, these findings suggest that the radiographic findings can present as a spectrum which can reflect a relative level of immunocompetence. This study warrants further evaluation in a larger and prospective cohort for validation.
CSIG-20. PROTEOGENOMICS PROFILING REVEALS ENRICHED PROTEIN TRANSLATION REGULATORS AS NEW THERAPEUTIC TARGETS IN DIPG
Authors: Arun Anguraj Vadivel, Sanja Pajovic, Lauren Phillips, Craig Simpson, Cunjie Zhang, Ying Bu, Mark Nitz, Michael Moran, Cynthia Hawkins
Journal: Neuro-Oncology (2022)

Abstract Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumor arising in the brainstems of children. Current therapies are ineffective resulting in a median survival rate of less than one year and it is the leading cause of brain tumor-related death in children. A novel mutation in histone H3 protein (H3K27M) was recently identified as a genetic initiation event and affects global K27 trimethylation on histone H3 proteins and DNA methylation. The epigenetic changes caused by H3K27M mutation suggest the existence of an H3K27M-specific transcriptome and proteome. We investigated DIPG tissues at the multi-omics level including total proteome, phosphoproteome, methylproteome and metabolome by mass spectrometry. A total of 30 patient tumours were profiled to identify differentially expressed proteins, differentially phosphorylated proteins, and differentially methylated proteins in tumour tissues compared to normal brains. We identified 2995 proteins that are differentially regulated, suggesting changes in key oncogenic pathways including negative regulation of apoptosis, translation, and metabolic pathways such as methionine salvage and TCA cycle in DIPG. The deregulation of these metabolic pathways due to the differentially expressed proteins in DIPG cells was confirmed by metabolomics studies. Protein phosphorylation and protein methylation profiling of DIPG implicated that translation-related proteins were the most highly modified (post-translationally) proteins in DIPG tissues. Furthermore, protein translation measured by CyTOF showed higher translation rates in DIPG and immortalized astrocytes carrying H3K27M than their WT counterparts. We investigated the functional consequence of knockdown of the highest methylated translation regulator EEF1A1 and its methyltransferase METTL13. ShRNA knockdown of both, EEF1A and METTL13 in DIPG cells significantly reduced the cell growth. Multi-omics analysis of DIPG highlighted regulation of protein translation as a potential therapeutic target.
NIMG-52. UTILITY OF ARTERIAL SPIN LABELING (ASL) AND DYNAMIC SUSCEPTIBILITY CONTRAST (DSC) PERFUSION MRI IMAGING IN DISTINGUISHING PSEUDOPROGRESSION IN GLIOBLASTOMA
Authors: Clifton Lewis, Lee Lucas, David Pozivilko, Frank Weng, Brian Livingston, Christine Lu-Emerson
Journal: Neuro-Oncology (2022)

Abstract Pseudoprogression is a radiographic phenomenon in which increase in post contrast enhancement can mimic tumor progression while actually representing treatment effect. This occurs in up to 30% of glioblastoma (GBM) patients, with higher rate in O6-methylguanine-DNA methyltransferase (MGMT) methylated patient, and may lead to premature discontinuation of therapy. Perfusion imaging, with either DSC and/or ASL can sometimes help differentiate between progression (Pr) versus pseudoprogression (PsPr) noninvasively. Between 2009-2019, we conducted a retrospective study of GBM patients diagnosed between 2009-2019 at Maine Medical Center who received standard of care (surgery/radiation/temozolomide), subsequently displayed changes concerning for progression (n=23) or pseudoprogression (n=3) within 12 months from completion of radiation, and who had a second resection for pathological assessment. Perfusion values were analyzed by assessing DSC ratios and grading ASL signal on MRI. 7/25 patients were MGMT methylated in the Pr group compared to 1/3 patients in the PsPr group. Both Pr and PsPr patients had similar mean DSC ratios (2.098 Pr and 2.200 PsPr, p = NS). Mean ASL grade was 2.4 for Pr patients versus 1.3 for PsPr patients, p = NS. ASL grades of 2 or higher had a sensitivity of 62% (95% CI [36, 83%]) and specificity of 33% (95% CI [6, 79%]) in distinguishing Pr from PsPr patients. DSC ratios of 1 or greater had a sensitivity of 96% (95% CI [80, 99%]) and specificity of 0% (95% CI [0, 66%]) for Pr versus PsPr patients. When both DSC ratios of 1 or greater and ASL grade of 2 or higher were combined, sensitivity remained high at 91% (95% CI [62, 98%]) with specificity of 0% (95% CI [0, 66%]). Despite the limited number of PsPr patients, results support the use of both DSC and ASL measurements to guide the determination of progression versus pseudoprogression in treated glioblastoma patients.
EXTH-44. PERSONALIZED IMMUNOTHERAPY VACCINES FOR GLIOBLASTOMA AND THEIR TREATMENT EFFICACY
Authors: Vrunda Trivedi, Changlin Yang, Graeme Fenton, Oleg Yegorov, Christina Von Roemeling, Kelena Klippel, Elizabeth Ogando-Rivas, Paul Castillo, Lan Hoang-Minh, Kyle Dyson, Ginger Moore, Duane Mitchell
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Glioblastoma multiforme (GBM) remains a disease with debilitating survival outcomes. Cancer immunogenomics represents a complementary approach to the application of genomics in developing novel immunotherapies for brain malignancies. Using a cancer immunogenomics approach that we developed, called the Open Reading Frame Antigen Network (O.R.A.N.), we identified the immunogenic neoantigens and tumor-associated antigens (TAAs) including cancer-testis and developmental antigens, that are aberrantly overexpressed in murine models of GBM. The aim of this study is to evaluate the immunologic effects and safety of immunotherapy vaccines targeting neoantigens and TAAs in preclinical models of GBM. METHODS RNAseq and WES were performed for murine glioblastoma tumors- KR158-Luc and GL261, and the results were fed to the O.R.A.N pipeline for antigen prediction. A tumor antigen-specific RNA library was created for each tumor using a gene enrichment strategy and validated by RNAseq. Tumor-bearing animals were treated with adoptively transferred ex vivo expanded lymphocytes and dendritic cell vaccines loaded with the tumor antigen-specific RNA. Tumor volume, and thus progress, was determined using in vivo luciferase imaging technique and the survival outcomes were noted. We also evaluated the efficacy of the tumor vaccines in combination with checkpoint blockade therapy by treating tumor-bearing animals with dendritic cell vaccines loaded with the tumor antigen-specific RNA combined with an anti-PD-1 antibody. RESULTS The dendritic cell vaccines loaded with tumor antigen-specific RNA were significantly effective in slowing the progression of murine GBM tumors in combination with both the adoptive cellular therapy as well as checkpoint blockade therapy. Additionally, we identified antigen-specific T cells targeting several of our predicted antigens and an increase in tumor-infiltrating lymphocytes and memory T cells in the treated animals. CONCLUSION We developed a dendritic cell-based vaccination approach targeting neoantigens and TAAs identified as being tumor-specific and evaluated the efficacy of immunotherapy vaccines in preclinical models of GBM.
CTNI-09. DIFFUSE MIDLINE GLIOMA-ADAPTIVE COMBINATORY TRIAL (DMG-ACT): A COMBINATION PLATFORM TRIAL IN PEDIATRIC AND YOUNG ADULT PATIENTS WITH DIFFUSE MIDLINE GLIOMA
Authors: Andrea Franson, Cassie Kline, Annette Molinaro, Yalan Zhang, Kelly Hitchner, Nalin Gupta, Carl Koschmann, Michael Prados, Javad Nazarian, Sabine Mueller
Journal: Neuro-Oncology (2022)

Abstract Despite advances in understanding the biology of diffuse midline gliomas (DMGs), clinical outcomes have not significantly improved. Therapy development is limited by: lack of preclinical data across multiple models and laboratories, limited knowledge about blood-brain barrier penetrance, and lack of multi-agent therapeutic approaches. We aimed to address these limitations by designing and implementing an innovative platform clinical trial (DMG-ACT). DMG-ACT is an open-label, multi-institutional, international trial of combination therapy for patients with DMG between 2 and 39 years of age. This study utilizes a novel Bayesian drug combination platform design with adaptive shrinkage (ComPAS). ComPAS allows for ongoing assessment of therapy efficacy with data borrowing across arms and the ability to eliminate ineffective drug combinations and add new promising combinations throughout the trial. The current treatment arms include ONC201 in combination with paxalisib. Patients enter one of three cohorts: newly-diagnosed (Cohort 1), post-radiation (Cohort 2), and relapsed/progressive (Cohort 3). Each cohort offers a target validation phase for patients who have not yet undergone biopsy to assess intratumoral pharmacokinetics/pharmacodynamics of pre-biopsy, single-agent dosing. Cohorts 1 and 3 offer radiation (Cohort 1) or re-irradiation (Cohort 3) with concomitant single-agent therapy followed by maintenance with combination therapy. The primary efficacy endpoints are median progression-free survival at 6 months (Cohorts 1 and 2) and overall survival at 7 months (Cohort 3). Exploratory endpoints include intratumoral drug concentrations; toxicity profile of combination therapy during radiation; toxicity profile and efficacy of combination therapy; CSF, ctDNA, stool, and flow cytometry biomarker analyses; and health related quality of life, cognitive, and patient/proxy-reported outcome measures. Additional therapy combinations that have shown additive or synergistic benefit in preclinical testing will be incorporated in future trial iterations and several are currently in development. The trial was launched in October 2021, with a total of 21 patients enrolled as of May 2022.
CTNI-12. PHASE II MULTICENTRIC ITALIAN TRIAL ON REPOSITIONING OF THE ANTIPSYCHOTIC DRUG CHLORPROMAZINE AND ITS COMBINATION WITH TEMOZOLOMIDE IN MGMT UNMETHYLATED GLIOBLASTOMA PATIENTS: THE RACTAC TRIAL
Authors: Andrea Pace, Giuseppe Lombardi, Silvia Matteoni, Veronica Villani, Dario Benincasa, Claudia Abruzzese, Giulia Cerretti, Mario Caccese, Antonio Silvani, Marco Giorgio Paggi
Journal: Neuro-Oncology (2022)

Abstract The poor prognosis of patients affected by glioblastoma (GBM) prompts the search for new and more effective therapies, particularly for GBMs with unmethylated MGMT. In this regard, drug repurposing, can represent a safe and inexpensive way to bring novel pharmacological approaches from bench to bedside. Chlorpromazine, a medication in use since six decades for the therapy of psychiatric disorders, shows in vitro features that make it eligible for repositioning in GBM therapy. In our experimentation on six GBM cell lines, chlorpromazine inhibited cell viability in an apoptosis-independent way, induced polyploidy, reduced cloning efficiency as well as neurosphere formation and downregulated the expression of stemness genes. Notably, we found that chlorpromazine synergized with temozolomide, in reducing cell viability and strongly cooperated in reducing cloning efficiency and inducing cell death in vitro for all the GBM cell lines assayed. With these assumptions, we started a multicentric Phase II clinical trial on newly diagnosed GBM patients with unmethylated MGMT by adding chlorpromazine to temozolomide in the adjuvant phase of the standard first-line therapeutic protocol. The experimental procedure involves the combination of CPZ with standard treatment with TMZ in the adjuvant phase of the Stupp protocol. CPZ is administered orally at a dose of 50 mg/day – GG 1-28 – of every cycle of the adjuvant treatment with TMZ. At present, 53 patients out of 60 patients planned have been enrolled, without relevant toxicity.